The amino acid residue at sequence position 5 in the conantokin peptides partially governs subunit-selective antagonism of recombinant N-methyl-D-aspartate receptors

The Journal of Biological Chemistry
R C KleinF J Castellino

Abstract

Whole cell voltage clamp recordings were performed to assess the ability of conantokin-G (con-G), conantokin-T (con-T), and a 17-residue truncated form of conantokin-R (con-R[1-17]) to inhibit N-methyl-d-aspartate (NMDA)-evoked currents in human embryonic kidney 293 cells transiently expressing various combinations of NR1a, NR1b, NR2A, and NR2B receptor subunits. Con-T and con-R[1-17] attenuated ion currents in cells expressing NR1a/NR2A or NR1a/NR2B. Con-G did not affect NMDA-evoked ionic currents in cells expressing NR1a/NR2A, but it showed inhibitory activity in cells expressing NR1a/NR2B receptors and the triheteromeric combination of NR1a/NR2A/NR2B. An Ala-rich con-G analog, con-G[Q6G/gamma7K/N8A/gamma10A/gamma14A/K15A/S16A/N17A] (Ala/con-G, where gamma is Gla), in which all nonessential amino acids were altered to Ala residues, manifested subunit specificity similar to that of con-G, suggesting that the replaced residues are not responsible for selectivity in the con-G framework. A sarcosine-containing con-T truncation analog, con-T[1-9/G1Src/Q6G], inhibited currents in NR1a/NR2A and NR1a/NR2B receptors, eliminating residues 10-21 as mediators of the broad subunit selectivity of con-T. In contrast to the null effects of c...Continue Reading

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Citations

Jul 25, 2006·Cell and Tissue Research·Georg Köhr
Aug 19, 2010·Pharmacological Reviews·Stephen F TraynelisRay Dingledine
Jun 9, 2004·European Journal of Biochemistry·Emma L MillardDavid J Craik
May 20, 2003·The Journal of Peptide Research : Official Journal of the American Peptide Society·R C KleinF J Castellino
Jul 1, 2004·Toxicon : Official Journal of the International Society on Toxinology·Wudayagiri RajendraKandiah Jeyaseelan
Sep 6, 2006·Toxicon : Official Journal of the International Society on Toxinology·Raymond S Norton, Baldomero M Olivera
Jan 6, 2005·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Elisa A Waxman, David R Lynch
Jul 22, 2014·Journal of Neuroscience Research·Luoxiu HuangFrancis J Castellino
Jun 22, 2005·The Journal of Biological Chemistry·Elisa A Waxman, David R Lynch
Dec 13, 2005·Journal of Neurochemistry·L RagnarssonD J Adams
Jun 9, 2006·Journal of Neurophysiology·Anitha B AlexKaren S Wilcox
Aug 4, 2006·Journal of Neurophysiology·Congyi LuStefano Vicini
Mar 13, 2012·Pharmacological Reviews·Richard J LewisMacDonald J Christie
Jan 13, 2004·Physiological Reviews·Heinrich Terlau, Baldomero M Olivera
Jan 21, 2014·Neuropharmacology·Rashna D BalsaraPatrick L Sheets

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